Compositions for preventing and/or treating degenerative disorders of the central nervous system and/or lysosomal storage disorders

ABSTRACT

The present invention provides novel compounds as well as compositions and methods using the same for preventing and/or treating degenerative disorders of the central nervous system and/or lysosomal storage disorders. In particular, the present invention provides methods for preventing and/or treating Parkinson&#39;s disease, Alzheimer&#39;s disease and/or Gaucher&#39;s disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage entry of PCT/US18/29275, filed onApr. 25, 2018, which claims priority to U.S. Application No. 62/489,621,filed on Apr. 25, 2017, both of which are incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

The present invention provides novel compounds, known as pharmacologicalchaperones, as well as compositions and methods using the same forpreventing and/or treating degenerative disorders of the central nervoussystem and/or lysosomal storage disorders. In particular, the presentinvention provides methods for preventing and/or treating Parkinson'sdisease, Alzheimer's disease and/or Gaucher's disease.

BACKGROUND OF THE INVENTION

Many degenerative disorders of the central nervous system are associatedwith pathologic aggregation of proteins or lipids. For example,synucleinopathies are a group of diseases that arise from disruption ofsynuclein protein homeostasis. In particular, alpha-synucleinaggregation is associated with pathological conditions characterized byLewy bodies, such as Parkinson's disease, dementia with Lewy bodies, andmultiple system atrophy. Likewise, alpha-synuclein fragment, non-Abetacomponent, is found in amyloid plaques of Alzheimer's disease. Recently,enhancement of glucocerebrosidase (beta-glucosidase; GCase) activity inthe brain has been shown to prevent accumulation of synuclein in thebrain (Sean Clark, Ying Sun, You-Hal Xu, Gregory Grabowski, and BrandonWustman, “A biochemical link between Gaucher's and Parkinson's diseaseand a potential new approach to treating synucleinopathies: apharmacological chaperone for beta-glucocerebrosidase preventsaccumulation of alpha-synuclein in a Parkinson's mouse model,” Presentedat the Society for Neuroscience Annual Meeting, San Diego, Calif.,2007). Thus, agents that enhance GCase activity may provide relief forpatients at risk for developing or diagnosed with degenerative disordersof the central nervous system.

Lysosomal storage disorders are caused by a defect in lysosomal functionthat results in accumulation of substances within the lysosome of cells.This defect is usually a consequence of deficiency of a single enzymerequired for the metabolism of lipid, glycogen, glycoprotein, ormucopolysaccharide. Gaucher's disease, the most common lysosomal storagedisorder, is characterized by accumulation of the glycolipidglucocerebroside (also known as glucosylceramide). Symptoms of Gaucher'sdisease include enlarged spleen and liver, liver malfunction, skeletaldisorders and bone lesions that may be painful, severe neurologiccomplications, swelling of lymph nodes and (occasionally) adjacentjoints, distended abdomen, a brownish tint to the skin, anemia, lowblood platelets and yellow fatty deposits on the sclera. In addition,persons affected with Gaucher's disease may also be more susceptible toinfection.

There is a need for new therapeutic compounds that can be used toprevent and/or treat degenerative disorders of the central nervoussystem and/or lysosomal storage disorders, which will provide patientswith a higher quality of life and achieve a better clinical outcome. Inparticular, there is a need for new therapeutic compounds to preventand/or treat synucleinopathies, such as Parkinson's disease andAlzheimer's disease, and lysosomal storage disorders such as Gaucher'sdisease, which will provide patients with a higher quality of life andachieve a better clinical outcome.

SUMMARY OF THE INVENTION

The present invention provides novel compounds as well as compositionsand methods using the same to prevent and/or treat a degenerativedisorder of the central nervous system and/or a lysosomal storagedisorder in a patient at risk for developing or diagnosed with the same,which includes administering to the patient in need thereof an effectiveamount of a compound described herein.

In one aspect, there is provided a compound as well as compositions andmethods using the same to prevent and/or treat a degenerative disorderof the central nervous system and/or a lysosomal storage disorder in apatient at risk for developing or diagnosed with the same, whichincludes administering to the patient in need thereof an effectiveamount of a compound defined by Formula I:

wherein:

-   -   R¹ is C(R²)(R³)(R⁴);    -   R² is hydrogen, —OH or halogen;    -   R³ is hydrogen, —OH, halogen or C₁₋₈ alkyl;    -   R⁴ is hydrogen, —OH, halogen, C₁₋₈ alkyl, substituted C₁₋₈        alkyl, aryl, substituted aryl, alkylcycloalkyl or substituted        alkylcycloalkyl;    -   R³ and R⁴ may join with the carbon to which they are attached to        form a cycloalkyl ring, which may be optionally substituted,        preferably with halogen and more preferably with one or more        fluorine atoms;    -   Z is optional, when present Z is —(CH₂)₁₋₈—, —C(═O)—,        —S(═O)₂NH—, —S(═O)₂—, —C(═S)NH—, —S(═O)₂—CH₃, C(═O)—NH—,        —S(═O)₂—NR¹²R¹³, —C(═O)C₁₋₈ alkyl or —C(═O)CH(NH₂)CH₃;    -   R¹² is hydrogen, C₁₋₈ alkyl or substituted C₁₋₈ alkyl;    -   R¹³ is hydrogen, C₁₋₈ alkyl or substituted C₁₋₈ alkyl;    -   R⁵ is hydrogen, C₁₋₈ alkyl, substituted C₁₋₈ alkyl, aryl,        substituted aryl, C₁₋₈ alkenyl, substituted C₁₋₈ alkenyl,        arylalkyl, substituted arylalkyl, alkylaryl, substituted        alkylaryl, aminoarylalkyl or substituted aminoarylalkyl;    -   R⁶ is hydrogen, halogen, C₁₋₈ alkyl, substituted C₁₋₈ alkyl,        arylalkyl, substituted arylalkyl, alkylaryl, or substituted        alkylaryl;    -   R⁷ is hydrogen, —OH or halogen;    -   R⁸ is hydrogen, halogen, C₁₋₈ alkyl, substituted C₁₋₈ alkyl,        arylalkyl, substituted arylalkyl, alkylaryl, or substituted        alkylaryl;    -   R⁹ is hydrogen, —OH or halogen;    -   R¹⁰ is hydrogen, halogen, C₁₋₈ alkyl, substituted C₁₋₈ alkyl,        arylalkyl, substituted arylalkyl, alkylaryl, or substituted        alkylaryl; and    -   R¹¹ is hydrogen, —OH or halogen,    -   provided that at least one of R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰ or        R¹¹ comprises a halogen.

In another aspect, there is provided a compound as well as compositionsand methods using the same to prevent and/or treat a degenerativedisorder of the central nervous system and/or a lysosomal storagedisorder in a patient at risk for developing or diagnosed with the same,which includes administering to the patient in need thereof an effectiveamount of a compound defined by Formula II:

wherein:

-   -   R¹ is C(R²)(R³)(R⁴);    -   R² is hydrogen, —OH or halogen;    -   R³ is hydrogen, —OH, halogen or —CH₃;    -   R⁴ is hydrogen, halogen, —CH₃, phenyl, fluorophenyl,        methylphenyl or cyclohexylmethyl;    -   R³ and R⁴ may join with the carbon to which they are attached to        form a cycloalkyl ring, which may be optionally substituted with        one or more halogen atoms;    -   Z is optional, when present Z is —(CH₂)—, —C(═O)—, —S(═O)₂NH—,        —S(═O)₂—, —S(═O)₂—CH₃, C(═O)—NH—, —S(═O)₂NR¹²R¹³, —C(═S)—NH— or        —C(═O)₂—CH₃,    -   R¹² is hydrogen or CH₃;    -   R¹³ is hydrogen or CH₃;    -   R⁵ is hydrogen or aminophenylalkyl;    -   R⁶ is hydrogen, halogen or —CH₃;    -   R⁷ is hydrogen, —OH or halogen;    -   R⁸ is hydrogen, halogen or —CH₃;    -   R⁹ is hydrogen, —OH or halogen;    -   R¹⁰ is hydrogen, halogen or —CH₃; and    -   R¹¹ is hydrogen, —OH or halogen;    -   provided that at least one of R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰ or        R¹¹ comprises a halogen.

In yet another aspect, there is provided a compound as well ascompositions and methods using the same to prevent and/or treat adegenerative disorder of the central nervous system and/or a lysosomalstorage disorder in a patient at risk for developing or diagnosed withthe same, which includes administering to the patient in need thereof aneffective amount of a compound defined by Formula III:

wherein:

-   -   R¹ is C(R²)(R³)(R⁴);    -   R² is hydrogen, —OH or halogen;    -   R³ is hydrogen, —OH, halogen or —CH₃;    -   R⁴ is hydrogen, halogen, —CH₃, phenyl, fluorophenyl,        methylphenyl or cyclohexylmethyl;    -   R³ and R⁴ may join with the carbon to which they are attached to        form a cycloalkyl ring, which may be optionally substituted with        one or more halogen atoms;    -   R⁶ is —OH or halogen;    -   R⁸ is —OH or halogen; and    -   R¹⁰ is —OH or halogen;    -   provided that that at least one of R², R³, R⁴, R⁶, R⁸ or R¹⁰        comprises a halogen.    -   It is understood by a person of ordinary skill in the art that        R², R³ and R⁴ in aforementioned Formulas I, II, and III will not        be selected such that an unstable molecule will result.

In still another aspect, there is provided a compound as well ascompositions and methods using the same to prevent and/or treat adegenerative disorder of the central nervous system and/or a lysosomalstorage disorder in a patient at risk for developing or diagnosed withthe same, which includes administering to the patient in need thereof aneffective amount of a compound selected from the following:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment, the compound is(1S,2S,3R,6S)-6-amino-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol,(1S,2S,3R,6R)-6-amino-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol,(1S,2S,3S,6S)-6-amino-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol,(1S,2S,3S,6R)-6-amino-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol or apharmaceutically acceptable salt, solvate, or prodrug thereof. In oneembodiment, the compound is(1S,2S,3R,6S)-6-amino-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol, or apharmaceutically acceptable salt, solvate, or prodrug thereof. In oneembodiment, the compound is(1S,2S,3R,6R)-6-amino-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol, or apharmaceutically acceptable salt, solvate, or prodrug thereof. In oneembodiment, the compound is((1S,2S,3S,6S)-6-amino-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol, or apharmaceutically acceptable salt, solvate, or prodrug thereof. In oneembodiment, the compound is((1S,2S,3S,6R)-6-amino-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol, or apharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment, the compound is(1S,2S,3R,6S)-6-amino-4-(difluoromethyl)cyclohex-4-ene-1,2,3-triol,(1S,2S,3R,6R)-6-amino-4-(difluoromethyl)cyclohex-4-ene-1,2,3-triol,(1S,2S,3S,6S)-6-amino-4-(difluoromethyl)cyclohex-4-ene-1,2,3-triol,(1S,2S,3S,6R)-6-amino-4-(difluoromethyl)cyclohex-4-ene-1,2,3-triol or apharmaceutically acceptable salt, solvate, or prodrug thereof. In oneembodiment, the compound is(1S,2S,3R,6S)-6-amino-4-(difluoromethyl)cyclohex-4-ene-1,2,3-triol, or apharmaceutically acceptable salt, solvate, or prodrug thereof. In oneembodiment, the compound is(1S,2S,3R,6R)-6-amino-4-(difluoromethyl)cyclohex-4-ene-1,2,3-triol, or apharmaceutically acceptable salt, solvate, or prodrug thereof. In oneembodiment, the compound is((1S,2S,3S,6S)-6-amino-4-(difluoromethyl)cyclohex-4-ene-1,2,3-triol, ora pharmaceutically acceptable salt, solvate, or prodrug thereof. In oneembodiment, the compound is((1S,2S,3S,6R)-6-amino-4-(difluoromethyl)cyclohex-4-ene-1,2,3-triol, ora pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment, the compound isN-((1S,4R,5S,6R)-3-(fluoromethyl)-4,5,6-trihydroxycyclohex-2-en-1-yl)acetamideor a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In one embodiment, the degenerative disorder is a synucleinopathy. Inone embodiment, the degenerative disorder is characterized by Lewybodies. In one embodiment, the degenerative disorder is Parkinson'sdisease, dementia with Lewy bodies, multiple system atrophy orAlzheimer's disease. In one embodiment, the degenerative disorder isassociated with aggregation of at least one protein. In one embodiment,the degenerative disorder is associated with aggregation ofalpha-synuclein. In one embodiment, the degenerative disorder isassociated with aggregation of non-Abeta component. In one embodiment,the degenerative disorder is associated with accumulation of at leastone glycolipid. In one embodiment, the degenerative disorder isassociated with accumulation of at least one glycosphingolipid. In oneembodiment, the degenerative disorder is associated with accumulation ofglucocerebroside. In one embodiment, the degenerative disorder isassociated with a mutation in glucocerebrosidase.

The present invention also provides methods for preventing and/ortreating a degenerative disorder of the central nervous system in apatient at risk for developing or diagnosed with the same, whichcomprises administering to the patient in need thereof an effectiveamount of any of the aforementioned compounds, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof, or any combination of twoor more thereof.

In one embodiment, the degenerative disorder of the central nervoussystem is an α-synucleinopathy. In one embodiment, the degenerativedisorder of the central nervous system is Parkinson's disease. In oneembodiment, the degenerative disorder of the central nervous system isAlzheimer's disease.

In one embodiment, the method of preventing and/or treating thedegenerative disorder of the central nervous system further comprisesadministering an effective amount of at least one other therapeuticagent. In one embodiment, at least one other therapeutic agent islevodopa, an anticholinergic, a catechol-O-methyl transferase inhibitor,a dopamine receptor agonist, a monoamine oxidase inhibitor, a peripheraldecarboxylase inhibitor, or an anti-inflammatory agent.

In one embodiment, the lysosomal storage disorder is associated withaccumulation of at least one glycolipid. In one embodiment, thelysosomal storage disorder is associated with accumulation of at leastone glycosphingolipid. In one embodiment, the lysosomal storage disorderis associated with accumulation of glucocerebroside. In one embodiment,the lysosomal storage disorder is associated with a deficiency inglucocerebrosidase. In one embodiment, the lysosomal storage disorder isassociated with a mutation in glucocerebrosidase. In one embodiment, thelysosomal storage disease is Niemann-Pick disease. In one embodiment,the lysosomal storage disease is Gaucher's disease.

The present invention also provides methods for preventing and/ortreating a lysosomal storage disorder in a patient at risk fordeveloping or diagnosed with the same, which comprises administering tothe patient in need thereof an effective amount of a compositioncomprising a compound of Formula I, or a pharmaceutically acceptablesalt, solvate, or prodrug thereof.

In one embodiment, the lysosomal storage disorder is Gaucher's disease.

In one embodiment, the method of preventing and/or treating a lysosomalstorage disorder further comprises administering an effective amount ofat least one other therapeutic agent. In one embodiment, at least oneother therapeutic agent is imiglucerase or1,5-(butylimino)-1,5-dideoxy-D-glucitol.

The present invention also provides kits comprising:

-   -   a container having an effective amount of any of the compounds        of the present invention, alone or in combination; and    -   instructions for using the same to prevent or treat a        degenerative disorder of the central nervous system or a        lysosomal storage disorder.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the following terms shall have the definitions set forthbelow.

As used herein, the phrase “degenerative disorder of the central nervoussystem” means any disorder associated with the premature degeneration ofany component of the central nervous system, such as neurons, myelinsheaths or axons. Such disorders include but are not limited tomulti-infarct dementia, Huntington's disease, Pick's disease,amyotrophic lateral sclerosis, Creutzfeldt-Jakob's disease, frontal-lobedegeneration, corticobasal degeneration, progressive supranuclear palsy,Parkinson's disease, dementia with Lewy bodies, multiple system atrophyor Alzheimer's disease.

As used herein the phrase “lysosomal storage disorder” refers to any ofa group of diseases resulting from abnormal metabolism resulting inaccumulation of a substrate in the lysosome. Table 1 contains anon-limiting list of exemplary lysosomal storage disorders and theirassociated defective enzyme.

TABLE 1 Lysosomal storage disorders Lysosomal storage disorder Defectiveenzyme Pompe disease Acid α-glucosidase Gaucher disease Acidβ-glucosidase or glucocerebrosidase Fabry disease α-Galactosidase AG_(M1)-gangliosidosis Acid β-galactosidase Tay-Sachs diseaseβ-Hexosaminidase A Sandhoff disease β-Hexosaminidase B Niemann-Pickdisease Acid sphingomyelinase Krabbe disease Galactocerebrosidase Farberdisease Acid ceramidase Metachromatic leukodystrophy Arylsulfatase AHurler-Scheie disease α-L-Iduronidase Hunter diseaseIduronate-2-sulfatase Sanfilippo disease A Heparan N-sulfataseSanfilippo disease B α-N-Acetylglucosaminidase Sanfilippo disease CAcetyl-CoA: α-glucosaminide N-acetyltransferase Sanfilippo disease DN-Acetylglucosamine-6-sulfate sulfatase Morquio disease AN-Acetylgalactosamine-6-sulfate sulfatase Morquio disease B Acidβ-galactosidase Maroteaux-Lamy disease Arylsulfatase B Sly diseaseβ-Glucuronidase alpha.-Mannosidosis Acid α-mannosidasebeta,-Mannosidosis Acid β-mannosidase Fucosidosis Acid α-L-fucosidaseSialidosis Sialidase Schindler-Kanzaki diseaseα-N-acetylgalactosaminidase

As used herein the term “treating” means to ameliorate one or moresymptoms associated with the referenced disorder.

As used herein, the term “preventing” means to mitigate a symptom of thereferenced disorder.

As used herein the phrase “an effective amount” means an amounteffective to prevent and/or treat a patient at risk for developing ordiagnosed with the referenced disorder, and thus producing the desiredtherapeutic effect.

As used herein the term “patient” means a mammal (e.g., a human).

Listed below are chemical definitions of various terms used to describethis invention. These definitions apply to the terms as they are usedthroughout this specification, unless otherwise limited in specificinstances, either individually or as part of a larger group.

The term “alkyl” refers to straight or branched chain unsubstitutedhydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 8 carbonatoms, more preferably 1 to 6 carbon atoms. The expression “lower alkyl”refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.

The term “substituted alkyl” refers to an alkyl group substituted by,for example, one to four substituents, such as, halo, hydroxy, alkoxy,oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino,aralkylamino, disubstituted amines in which the 2 amino substituents areselected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino,aralkanoylamino, substituted alkanoylamino, substituted arylamino,substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio,alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl,aralkylsulphonyl, sulfonamido, e.g. SO₂NH₂, substituted sulfonamido,nitro, cyano, carboxy, carbamyl, e.g. CONH₂, substituted carbamyl e.g.CONHalkyl, CONHaryl, CONHaralkyl or cases where there are twosubstituents on the nitrogen selected from alkyl, aryl or aralkyl;alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, suchas, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,pyrimidyl and the like. Where noted above where the substituent isfurther substituted it will be with alkyl, alkoxy, aryl or aralkyl.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6 to 12 carbon atoms in the ring portion, such as phenyl,naphthyl, biphenyl and diphenyl groups, each of which may besubstituted.

The term “aralkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl. Similarly, the term “alkylaryl” refers toan alkyl group bonded directly through an aryl group, such asmethylbenzyl.

The term “substituted aryl” refers to an aryl group substituted by, forexample, one to four substituents such as alkyl, substituted alkyl,halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl,alkanoyloxy, amino, alkylamino, aralkylamino, dialkylamino,alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxy,carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono,arylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, aryloxy andthe like. The substituent may be further substituted by hydroxy, alkyl,alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.

The term “heteroaryl” refers to an optionally substituted, aromaticgroup for example, which is a 4 to 7 membered monocyclic, 7 to 11membered bicyclic, or 10 to 15 membered tricyclic ring system, which hasat least one heteroatom and at least one carbon atom-containing ring,for example, pyridine, tetrazole, indazole.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, andmost preferably 2 to 8 carbon atoms, having one to four double bonds.

The term “substituted alkenyl” refers to an alkenyl group substitutedby, for example, one to two substituents, such as, halo, hydroxy,alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino,alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl,sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl,guanidino, indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl,pyridyl, pyrimidyl and the like.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, andmost preferably 2 to 8 carbon atoms, having one to four triple bonds.

The term “substituted alkynyl” refers to an alkynyl group substitutedby, for example, a substituent, such as, halo, hydroxy, alkoxy,alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino,thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano,carboxy, carbamyl, substituted carbamyl, guanidino and heterocyclo, e.g.imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyland the like.

The term “cycloalkyl” refers to an optionally substituted, saturatedcyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and3 to 7 carbons per ring which may be further fused with an unsaturatedC3-C7 carbocylic ring. Exemplary groups Include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl,cyclododecyl, and adamantyl. Exemplary substituents include one or morealkyl groups as described above, or one or more groups described aboveas alkyl substituents.

The terms “heterocycle”, “heterocyclic” and “heterocyclo” refer to anoptionally substituted, fully saturated or unsaturated, aromatic ornonaromatic cyclic group, for example, which is a 4 to 7 memberedmonocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclicring system, which has at least one heteroatom in at least one carbonatom-containing ring. Each ring of the heterocyclic group containing aheteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms,oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatomsmay also optionally be oxidized and the nitrogen heteroatoms may alsooptionally be quaternized. The heterocyclic group may be attached at anyheteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl,azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, and triazolyl, and the like.

Exemplary bicyclic hetrocyclic groups include2,3-dihydro-2-oxo-1H-indolyl, benzothiazolyl, benzoxazolyl,benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,1-b]pyridinyl or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl, and the like.

Exemplary substituents include one or more alkyl or aralkyl groups asdescribed above or one or more groups described above as alkylsubstituents.

Also included are smaller heterocyclos, such as, epoxides andaziridines.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

Degenerative Disorders of the Central Nervous System

Parkinson's disease may be diagnosed in patients according to the UnitedKingdom Parkinson's Disease Society brain-bank clinical diagnosticcriteria (see, Hughes et al., Accuracy of clinical diagnosis ofidiopathic Parkinson's disease: a clinico-pathological study of 100cases. J Neurol Neurosurg Psychiatry 1992; 55:181-184) and/or thecriteria described by Gelb et al., Diagnostic Criteria for Parkinson'sDisease. Arch Neurol. 1999; 56(1):33-39. Likewise, the severity ofParkinson's disease may be ascertained using the Unified Parkinson'sDisease Rating Scale. See, e.g., Fahn and Elton, Members of the UnifiedParkinson's Disease Rating Scale Development Committee. UnifiedParkinson's Disease Rating Scale. In: Fahn et al., Recent developmentsin Parkinson's disease. New York: Macmillan, 1987: 153-183.

Alzheimer's disease may be diagnosed in patients according to thecriteria for dementia of the Alzheimer's type of the Diagnostic andStatistical Manual of Mental Disorders, 4^(th) ed.: DSM-IV. Washington,D.C.: American Psychiatric Association, 1994. Likewise, the criteria forprobable Alzheimer's disease may be ascertained based on criteria of theNational Institute of Neurological and Communicative Disorders andStroke and the Alzheimer's Disease and Related Disorders Association.See also, McKhann et al., Clinical diagnosis of Alzheimer's disease:report of the NINCDS-ADRDA work group under the auspices of Departmentof Health and Human Services Task Force on Alzheimer's Disease.Neurology 1984; 34:939-944.

Multiple system atrophy (MSA) is characterized by glial cytoplasmicinclusion bodies (also known as Papp-Lantos bodies) in the movement,balance and automatic control centers of the brain. The most commonfirst sign of MSA is the appearance of an “akinetic-rigid syndrome”(i.e., slowness of initiation of movement resembling Parkinson'sdisease) found in 62% at first presentation. Other common signs at onsetinclude problems with balance (found in 22%), followed by genito-urinaryproblems (9%). For men, the first sign can be erectile dysfunction(unable to achieve or sustain an erection). Both men and women oftenexperience problems with their bladders including urgency, frequency,incomplete bladder emptying or an inability to pass urine (retention).About 1 in 5 MSA patients will suffer a fall in their first year ofdisease. As the disease progresses three groups of symptoms predominate.These are: (i) parkinsonism (slow, stiff movement, writing becomes smalland spidery); (ii) cerebellar dysfunction (difficulty coordinatingmovement and balance); and (iii) autonomic dysfunction (impairedautomatic body functions) including: postural or orthostatichypotension, resulting in dizziness or fainting upon standing up,urinary incontinence, impotence; constipation; dry mouth and skin;trouble regulating body temperature due to abnormal sweating; abnormalbreathing during sleep. Notably, not all of these symptoms areexperienced by all patients.

Dementia with Lewy bodies (DLB) is one of the most common types ofprogressive dementia. The central feature of DLB is progressivecognitive decline, combined with three additional defining features: (1)pronounced “fluctuations” in alertness and attention, such as frequentdrowsiness, lethargy, lengthy periods of time spent staring into space,or disorganized speech; (2) recurrent visual hallucinations, and (3)parkinsonian motor symptoms, such as rigidity and the loss ofspontaneous movement. People may also suffer from depression. Thesymptoms of DLB are caused by the build-up of Lewy bodies—accumulatedbits of alpha-synuclein protein—inside the nuclei of neurons in areas ofthe brain that control particular aspects of memory and motor control.Researchers don't know exactly why alpha-synuclein accumulates into Lewybodies or how Lewy bodies cause the symptoms of DLB, but they do knowthat alpha-synuclein accumulation is also linked to Parkinson's disease,multiple system atrophy, and several other disorders, which are referredto as the “synucleinopathies.” The similarity of symptoms between DLBand Parkinson's disease, and between DLB and Alzheimer's disease, canoften make it difficult for a doctor to make a definitive diagnosis. Inaddition, Lewy bodies are often also found in the brains of people withParkinson's and Alzheimer's diseases. These findings suggest that eitherDLB is related to these other causes of dementia or that an individualcan have both diseases at the same time. DLB usually occurssporadically, in people with no known family history of the disease.However, rare familial cases have occasionally been reported.

Lysosomal Storage Disorders

The most common lysosomal storage disorder, Gaucher's disease, ischaracterized by accumulation of the glycolipid glucocerebroside (alsoknown as glucosylceramide). Three phenotypes have been described forGaucher's disease that are denoted by the absence (type 1) or presenceof neurologic involvement during childhood (type 2) or adolescence (type3). For example, see Grabowski, Gaucher's disease. Adv Hum Genet 1993;21:377-441.

The three types of Gaucher's disease are inherited in an autosomalrecessive fashion. Both parents must be carriers in order for a child tobe affected. If both parents are carriers, there is a one in four, or25%, chance with each pregnancy for an affected child. Geneticcounseling and genetic testing is recommended for families who may becarriers of mutations. Each type has been linked to particularmutations. In all, there are about 80 known mutations that lead toGaucher's disease (see, e.g., McKusick, V. A.: Mendelian Inheritance inMan. A Catalog of Human Genes and Genetic Disorders. Baltimore: JohnsHopkins University Press, 1998 (12th edition)).

Type 1 Gaucher's disease is panethnic, but is especially prevalent amongpersons of Ashkenazi Jewish descent, with a carrier rate of 1 in 17Ashkenazi Jews. The N370S and 84GG mutations are the most frequentmutations in the glucocerebrosidase gene among Ashkenazi Jews, withrates of 1 in 17.5 for N370S and 1 in 400 for 84GG in the generalhealthy Ashkenazi population, and are associated with mild and severeGaucher's disease, respectively. The 84GG mutation occurs almostexclusively among Ashkenazi Jews. Other rare glucocerebrosidase genevariants identified in patients of Ashkenazi descent with Gaucher'sdisease include L444P, IVS2+1G→A, V394L, and R496H. In contrast topresentation of Type 1 Gaucher's disease in Ashkenazi Jews, Type 1Gaucher's disease tends to be severe and progressive in Japanesepatients (see, Ida et al., Type 1 Gaucher Disease Patients: PhenotypicExpression and Natural History in Japanese Patients, Blood Cells,Molecules and Diseases, 1984, 24(5):73-81). In addition, Type 3Gaucher's disease, associated with one or two copies ofglucocerebrosidase gene variant L444P is prevalent in Swedish patientsfrom the Norrbotten region.

A definitive diagnosis of Gaucher's disease is made with genetictesting. As there are numerous different mutations, sequencing of theglucocerebrosidase gene is sometimes necessary to confirm the diagnosis.Prenatal diagnosis is available, and is useful when there is a knowngenetic risk factor. However, a diagnosis of Gaucher's disease can alsobe implied by biochemical abnormalities such as high alkalinephosphatase, angiotensin-converting enzyme (ACE) and immunoglobulinlevels, or by cell analysis showing “crinkled paper” cytoplasm andglycolipid-laden macrophages. Notably, Niemann-Pick disease is similarin that it is characterized by accumulation of G_(M2)-gangliosides andG_(M1)-gangliosides in addition to glucocerebroside (Vanier et al.,Brain Pathology. 1998; 8: 163-74).

Symptoms of Gaucher's disease include the following:

-   -   Painless hepatomegaly and splenomegaly (the size of the spleen        can be 1500-3000 ml, as opposed to the normal size of 50-200 ml)    -   Hypersplenism: the rapid and premature destruction of blood        cells, leading to anemia, neutropenia and thrombocytopenia (with        an increased risk of infection and bleeding)    -   Cirrhosis of the liver, though rare    -   Neurological symptoms occur only in some types of Gaucher's (see        below):        -   Type II: serious convulsions, hypertonia, mental            retardation, apnea.        -   Type III: muscle twitches known as myoclonus, convulsions,            dementia, ocular muscle apraxia.    -   Osteoporosis: 75% develop visible bony abnormalities due to the        accumulated glucosylceramide. A deformity of the distal femur in        the shape of an Erlenmeyer flask is commonly described.    -   Yellowish-brown skin pigmentation        Compounds

Novel compounds of the present invention are provided below:

Chemical Process

Synthesis of the valienamine core can be accomplished using variouspathways described in the art (See. e.g., Kok et al. (2001). “A NewSynthesis of Valienamine,” J. Org. Chem. 66:7184-90). Compositions ofthe present invention can be synthesized by halogenation during thevalienamine synthesis process.

One exemplary synthesis is shown in Process Scheme 1. It is understoodby a person of ordinary skill in the art that the desiredstereochemistry and constituents of the desired product can be obtainedusing analogous reagents and substitutions in the appropriate stage ofthe synthesis pathway.

Salts, Solvates and Prodrugs

Compounds of the present invention include pharmaceutically acceptablesalts, solvates and pro-drugs of the compounds disclosed herein.Pharmaceutically acceptable salts include salts derived from inorganicbases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic basessuch as N,N′-diacetylethylenediamine, glucamine, triethylamine, choline,hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine,thiamine; chiral bases like alkylphenylamine, glycinol, phenyl glycinol,salts of natural amino acids such as glycine, alanine, valine, leucine,isoleucine, norleucine, tyrosine, cystine, cysteine, methionine,proline, hydroxy proline, histidine, omithine, lysine, arginine, serine;non-natural amino acids such as D-isomers or substituted amino acids;guanidine, substituted guanidine wherein the substituents are selectedfrom nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substitutedammonium salts and aluminum salts. Salts may include acid addition saltswhere appropriate which are, hydrochlorides, sulphates, nitrates,phosphates, perchlorates, borates, hydrohalides, acetates, tartrates,maleates, citrates, succinates, palmoates, methanesulphonates,benzoates, salicylates, benzenesulfonates, ascorbates,glycerophosphates, ketoglutarates. In one embodiment, thepharmaceutically acceptable salt of the compounds disclosed herein isthe hydrochloride salt.

“Solvate” denotes a physical association of a compound with one or moresolvent molecules. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances the solvate will be capable of isolation, for example when oneor more solvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. “Hydrate” is a solvate wherein the solvent moleculeis H₂O. Other non-limiting examples of suitable solvates includealcohols (e.g., ethanolates, methanolates, and the like).

Prodrugs are compounds which are converted in vivo to active forms (see,e.g., R. B. Silverman, 1992, “The Organic Chemistry of Drug Design andDrug Action”, Academic Press, Chapter 8, incorporated herein byreference). Additionally, a discussion of prodrugs is provided in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Volume 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencethereto. Prodrugs can be used to alter the biodistribution (e.g., toallow compounds which would not typically enter the reactive site of theprotease) or the pharmacokinetics for a particular compound. Forexample, a carboxylic acid group, can be esterified, e.g., with a methylgroup or an ethyl group to yield an ester. When the ester isadministered to a subject, the ester is cleaved, enzymatically ornon-enzymatically, reductively, oxidatively, or hydrolytically, toreveal the anionic group. An anionic group can be esterified withmoieties (e.g., acyloxymethyl esters) which are cleaved to reveal anintermediate compound which subsequently decomposes to yield the activecompound.

Examples of prodrugs and their uses are well known in the art (See,e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.68:1-19). The prodrugs can be prepared in situ during the finalisolation and purification of the compounds, or by separately reactingthe purified compound with a suitable derivatizing agent. For examplehydroxy groups can be converted into esters via treatment with acarboxylic acid in the presence of a catalyst. Examples of cleavablealcohol prodrug moieties include substituted and unsubstituted, branchedor unbranched lower alkyl ester moieties, (e.g., ethyl esters), loweralkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g.,dimethylaminoethyl ester), acylamino lower alkyl esters, acyloxy loweralkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenylester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g.,with methyl, halo, or methoxy substituents) aryl and aryl-lower alkylesters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxyamides.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the compounds disclosed herein (including those of thesalts, solvates and prodrugs of these compounds as well as the salts andsolvates of the prodrugs), such as those which may exist due toasymmetric carbons on various substituents, including enantiomeric forms(which may exist even in the absence of asymmetric carbons), rotamericforms, atropisomers, and diastereomeric forms, are contemplated withinthe scope of this invention. Individual stereoisomers of these compoundsmay, for example, be substantially free of other isomers, or may beadmixed, for example, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the aforementioned compounds canhave the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate” “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the compounds of the present invention disclosed herein.

Formulations

The therapeutic agent(s) can be formulated to be suitable for any routeof administration, including e.g., orally in the form of tablets orcapsules or liquid, or in sterile aqueous solution for injection. Whenthe therapeutic agent(s) is formulated for oral administration, tabletsor capsules can be prepared by conventional means with pharmaceuticallyacceptable excipients such as binding agents (e.g., pregelatinized maizestarch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers(e.g., lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g., magnesium stearate, talc or silica);disintegrants (e.g., potato starch or sodium starch glycolate); orwetting agents (e.g., sodium lauryl sulphate). The tablets may be coatedby methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or another suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with pharmaceuticallyacceptable additives such as suspending agents (e.g., sorbitol syrup,cellulose derivatives or hydrogenated edible fats); emulsifying agents(e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oilyesters, ethyl alcohol or fractionated vegetable oils); or preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The liquidpreparations may also contain buffer salts, flavoring, coloring orsweetening agents as appropriate. Preparations for oral administrationmay be suitably formulated to give controlled or sustained release ofthe therapeutic agent(s).

In certain embodiments of the present invention, the therapeuticagent(s) is administered in a dosage form that permits systemic uptake,such that the therapeutic agent(s) may cross the blood-brain barrier soas to exert effects on neuronal cells. For example, pharmaceuticalformulations of the therapeutic agent(s) suitable forparenteral/injectable use generally include sterile aqueous solutions(where water soluble), or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersion. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol,polyethylene glycol, and the like), suitable mixtures thereof, orvegetable oils. The proper fluidity can be maintained, for example, bythe use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. Prevention of the action of microorganisms can be broughtabout by various antibacterial and antifungal agents, for example,parabens, chlorobutanol, phenol, benzyl alcohol, sorbic acid, and thelike. In many cases, it will be reasonable to include isotonic agents,for example, sugars or sodium chloride. Prolonged absorption of theInjectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonosterate or gelatin.

Sterile injectable solutions are prepared by incorporating thetherapeutic agent(s) in the required amount in the appropriate solventwith various of the other ingredients enumerated above, as required,followed by filter or terminal sterilization. Generally, dispersions areprepared by incorporating the various sterilized active Ingredients intoa sterile vehicle which contains the basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze-dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from previously sterile-filtered solutionthereof.

The formulation can contain an excipient. Pharmaceutically acceptableexcipients which may be included in the formulation are buffers such ascitrate buffer, phosphate buffer, acetate buffer, and bicarbonatebuffer, amino acids, urea, alcohols, ascorbic acid, phospholipids;proteins, such as serum albumin, collagen, and gelatin; salts such asEDTA or EGTA, and sodium chloride; liposomes; polyvinylpyrollidone;sugars, such as dextran, mannitol, sorbitol, and glycerol; propyleneglycol and polyethylene glycol (e.g., PEG-4000, PEG-6000); glycerol;glycine or other amino acids; and lipids. Buffer systems for use withthe formulations include citrate; acetate; bicarbonate; and phosphatebuffers. Phosphate buffer is a preferred embodiment.

The formulation can also contain a non-ionic detergent. Preferrednon-ionic detergents include Polysorbate 20, Polysorbate 80, TritonX-100, Triton X-114, Nonidet P-40, Octyl α-glucoside, Octyl β-glucoside,Brij 35, Pluronic, and Tween 20.

Routes of Administration

The therapeutic agent(s) may be administered orally or parenterally,including intravenously, subcutaneously, intra-arterially,intraperitoneally, ophthalmically, intramuscularly, buccally, rectally,vaginally, intraorbitally, intracerebrally, intradermally,intracranially, intraspinally, intraventricularly, intrathecally,intracistemally, intracapsularly, intrapulmonarily, intranasally,transmucosally, transdermally, or via inhalation. In one preferredembodiment, the therapeutic agent(s) is administered orally.

Administration of therapeutic agent(s) may be by periodic injections ofa bolus of the formulation, or may be administered by intravenous orintraperitoneal administration from a reservoir which is external (e.g.,an i.v. bag) or internal (e.g., a bioerodible implant). See, e.g., U.S.Pat. Nos. 4,407,957 and 5,798,113, each incorporated herein byreference. Intrapulmonary delivery methods and apparatus are described,for example, in U.S. Pat. Nos. 5,654,007, 5,780,014, and 5,814,807, eachincorporated herein by reference. Other useful parenteral deliverysystems include ethylene-vinyl acetate copolymer particles, osmoticpumps, implantable infusion systems, pump delivery, encapsulated celldelivery, liposomal delivery, needle-delivered injection, needle-lessinjection, nebulizer, aerosolizer, electroporation, and transdermalpatch. Needle-less injector devices are described in U.S. Pat. Nos.5,879,327; 5,520,639; 5,846,233 and 5,704,911, the specifications ofwhich are herein incorporated by reference. Any of the formulationsdescribed above can be administered using these methods.

Subcutaneous injections have the advantages allowingself-administration, while also resulting in a prolonged plasmahalf-life as compared to Intravenous administration. Furthermore, avariety of devices designed for patient convenience, such as refillableinjection pens and needle-less injection devices, may be used with theformulations of the present invention as discussed herein.

Dosage

A suitable pharmaceutical preparation is in a unit dosage form. In suchform, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose. In certain embodiments,the therapeutic agent(s) is administered in one or more daily doses(e.g., once-a-day, twice-a-day, thrice-a-day). In certain embodiments,the therapeutic agent(s) is administered in Intermittently.

Exemplary dosing regimens are described in International patentapplication PCT/US08/61764 published as WO 2008/134628 on Jun. 11, 2008and U.S. provisional patent application 61/108,192, filed on Oct. 24,2008, both of which are incorporated by reference herein in theirentirety. In one embodiment, the therapeutic agent(s) is administered inan intermittent dosing regimen that includes an initial “loading dose”given daily, followed by a period of non-daily Interval dosing.

The amount of effective therapeutic agent(s) for preventing or treatingthe referenced disorder can be determined on a case-by-case basis bythose skilled in the art. The amount and frequency of administration ofthe therapeutic agent(s) will be regulated according to the judgment ofthe attending clinician (physician) considering such factors as age,condition and size of the patient as well as risk for developingdisorder or severity of the symptoms of the referenced disorder beingtreated.

Combination Drug Therapy

The therapeutic agent(s) of the present invention can be administered incombination with at least one other therapeutic agent. Administration ofthe therapeutic agent(s) of the present invention with at least oneother therapeutic agent is understood to encompass administration thatis sequential or concurrent. In one embodiment, the therapeutic agentsare administered in separate dosage forms. In another embodiment, two ormore therapeutic agents are administered concurrently in the same dosageform.

In certain embodiments, the therapeutic agent(s) of the presentinvention are administered in combination with at least one othertherapeutic agent which is an anti-dyskinesia Agent (e.g., Carbidopa,Levodopa), an anti-infective agent (e.g., Miglustat), an antineoplasticagent (e.g., Busulfan, Cyclophosphamide), a gastrointestinal agent(e.g., Methylprednisolone), a micronutrient (e.g., Calcitriol,Cholecalciferol, Ergocalciferols, Vitamin D), a vasoconstrictor agent(e.g., Calcitriol).

In certain embodiments, the therapeutic agent(s) of the presentinvention are administered in combination with allopregnanolone, alow-cholesterol diet, or cholesterol-lowering agents such as statins(e.g., Lipitor®); fibrates such as fenofibrate (Lipdil®); niacin; and/orbinding resins such as cholestyramine (Questran®).

In one embodiment, the therapeutic agent(s) of the present invention isadministered in combination with gene therapy. Gene therapy iscontemplated both with replacement genes such as glucocerebrosidase orwith inhibitory RNA (siRNA) for the SNCA gene. Gene therapy is describedin more detail in U.S. Pat. No. 7,446,098, filed on Feb. 17, 2004.

In one embodiment, the therapeutic agent(s) of the present invention isadministered in combination with at least one other therapeutic agentwhich is an anti-inflammatory agent (e.g., ibuprofen or other NSAID).

In one embodiment, the therapeutic agent(s) of the present invention isadministered in combination with a substrate inhibitor forglucocerebrosidase, such as N-butyl-deoxynojimycin (Zavesca®; miglustatavailable from Actelion Pharmaceuticals, US, Inc., South San Francisco,Calif., US).

Combinations of the therapeutic agent(s) of the present invention withat least one other therapeutic agent which is a therapeutic agent forone or more other lysosomal enzymes are also contemplated. Table 2 is anon-limiting list of therapeutic agents for lysosomal enzymes.

TABLE 2 LYSOSOMAL ENZYME THERAPEUTIC AGENT α-Glucosidase1-deoxynojirimycin (DNJ) GenBank Accession No. a-homonojirimycin Y00839castanospermine Acid β-Glucosidase (β- isofagomine glucocerebrosidase)C-benzyl isofagomine and derivatives GenBank Accession No. N-alkyl(C9-12)-DNJ J03059 Glucoimidazole (and derivatives) C-alkyl-IFG (andderivatives) N-alkyl-β-valeinamines Fluphenozine calystegines A₃, B₁, B₂and C₁ α-Galactosidase A 1-deoxygalactonojirimycin (DGJ) GenBankAccession No. α-allo-homonojirimycin NM000169 α-galacto-homonojirimycinβ-1-C-butyl-deoxynojirimycin calystegines A₂ and B₂ N-methylcaiystegines A₂ and B₂ Acid β-Galactosidase 4-epi-isofagomine GenBankAccession No. 1-deoxygalactonojirimyion M34423 Galactocerebrosidase4-epi-isofagomine (Acid β- 1-deoxygalactonojirimycin Galactosidase)GenBank Accession No. D25283 Acid α-Mannosidase 1-deoxymannojirimycinGenBank Accession No. Swainsonine U68567 Mannostatin A Acidβ-Mannosidase 2-hydroxy-isofagomine GenBank Accession No. U60337 Acidα-L-fucosidase 1-deoxyfuconojirimycin GenBank Accession No.β-homofuconojirimycin NM_000147 2,5-imino-1,2,5-trideoxy-L-glucitol2,5-deoxy-2,5-imino-D-fucitol 2,5-imino-12,5-trideoxy-D-altritolα-N-Acetylglucosaminidase 1,2-dideoxy-2-N-acetamido-nojirimycin GenBankAccession No. U40846 α-N-Acetylgalactosaminidase1,2-dideoxy-2-N-acetamido- GenBank Accession No. galactonojirimycinM62783 β-Hexosaminidase A 2-N-acetylamino-isofagomine GenBank AccessionNo. 1,2-dideoxy-2-acetamido-nojirimycin NM_000520 Nagstatinβ-Hexosaminidase B 2-N-acetamido-isofagomine GenBank Accession No.1,2-dideoxy-2-acetamido-nojirimycin NM_000521 Nagstatin α-L-Iduronidase1-deoxyiduronojirimycin GenBank Accession No.2-carboxy-3,4,5-trideoxypiperidine NM_000203 β-Glucuronidase6-carboxy-isofagomine GenBank Accession No.2-carboxy-3,4,5-trideoxypiperidine NM_000181 Sialidase 2,6-dideoxy-2,6,imino-sialic acid GenBank Accession No. Siastatin B U84246 Iduronatesulfatase 2,5-anhydromannitol-6-sulphate GenBank Accession No. AF_011889Acid sphingomyelinase desipramine, phosphatidylinositol-4,5- GenBankAccession No. diphosphate M59916

In certain embodiments, the therapeutic agent(s) of the presentinvention are administered in combination with at least one therapeuticagent which is an anti-dyskinesia Agent (e.g., Carbidopa, Levodopa), ananti-infective agent (e.g., Cyclosporine, Miglustat, Pyrimethamine), anantineoplastic agent (e.g., Alemtuzumab, Azathioprine, Busulfan,Clofarabine, Cyclophosphamide, Melphalan, Methotrexate, Rituximab), anantirheumatic agent (e.g., Rituximab) a gastrointestinal agent (e.g.,Methylprednisolone), a micronutrient (e.g., Calcitriol, Cholecalciferol,Ergocalciferols, Folic Acid, Vitamin D), a reproductive control agent(e.g., Methotrexate), a respiratory system agent (e.g.,Tetrahydrozoline), vasoconstrictor agent (e.g., Calcitriol,Tetrahydrozoline).

In certain embodiments, the therapeutic agent(s) of the presentinvention are administered in combination with at least one therapeuticagent which is a therapeutic agent for β-hexosaminidase A and/or atherapeutic agent for acid β-galactosidase. In certain embodiments, thetherapeutic agent(s) of the present invention are administered incombination with at least one therapeutic agent which is ananti-Infective agent (e.g., Miglustat), an antineoplastic agent (e.g.,Alemtuzumab, Busulfan, Cyclophosphamide), a gastrointestinal agent(e.g., Methylprednisolone).

The therapeutic agent(s) of the present invention can be administered incombination with at least one other therapeutic agent which includes butis not limited to, RNAi, dopamine replacement (e.g., levodopa (L-DOPA)),dopamine replacement stabilizer (e.g., carbidopa, and entacapone),anticholinergic (e.g., trihexyphenidyl, benzatropine mesylate(Cogentin®), trihexyphenidyl HCL (Artane®), and procyclidine),catechol-O-methyltransferase (COMT) Inhibitor (e.g., entacapone(Comtan®) and tolcapone (Tasmar®)), dopamine receptor agonist (e.g.,bromocriptine (Parlodel®), pramipexole (Mirapex®), ropinirole(Requip®)), pergolide (Permax), and APOKYN™ injection (apomorphinehydrochloride), monoamine oxidase (MAO) inhibitor (i.e., MAO-A and/orMAO-B inhibitors, e.g., selegiline (Deprenyl, Eldepryl®, Carbex®),selegiline HCl orally disintegrating tablet (Zelapar®), and rasagiline(Azilect®)), peripheral decarboxylase inhibitor, amantadine(Symmetrel®), and rivastigmine tartrate (Exelon®).

Also contemplated are combinations of the therapeutic agent(s) of thepresent invention with more than one other therapeutic agent. Exemplarycombinations of other therapeutic agents include, but not are notlimited to, carbidopa/levodopa (Sinemet® or Parcopa®), carbidopa,levodopa and entacapone (Stalevo®), levodopa with a dopamine receptoragonist such as bromocriptine (Parlodel®), pramipexole (Mirapex®),ropinirole (Requip®)), pergolide (Permax), or APOKYN™ injection(apomorphine hydrochloride).

In one embodiment, the therapeutic agent(s) of the present invention isadministered in combination with vaccine therapy, such as a vaccinecomprising alpha-synuclein and an adjuvant (Pilcher et al., LancetNeurol. 2005; 4(8):458-9).

In one embodiment, the therapeutic agent(s) of the present invention isadministered in combination with at least one other therapeutic agentthat may be protective such as dextromethorphan (Li et al., FASEB J.2005; April; 19(6):489-96); genistein (Wang et al., Neuroreport. 2005;February 28; 16(3):267-70), or minocycline (Blum et al., Neurobiol Dis.2004; December; 17(3):359-66).

In one embodiment, the therapeutic agent(s) of the present invention isadministered in combination with at least one other therapeutic agentwhich is therapeutic agent for alpha-synuclein (e.g., Hsp70).

Patients having Parkinson's disease experience tremor, rigidity,bradykinesia, and postural imbalance. Patients having Lewy Body Dementiaexperience strong psychotic symptoms (visual hallucinations) in additionto mental decline such as memory loss and an inability to carry outsimple tasks. Observable improvements in symptoms, or a delay of onsetof certain symptoms in patients at risk of developing a disorder, or adelay in progression of the disorder will be evidence of a favorableresponse to the therapies provided herein.

In addition, measurable surrogate markers also may be useful forevaluating response to therapy. For instance, some investigators havereported detecting higher levels of alpha-synuclein or oligomeric formsof alpha-synuclein have been detected in the plasma of patients withParkinson's disease (Lee et al., J Neural Transm. 2006; 113(10):1435-9;El-Agnaf et al., FASEB J. 2006; 20(3):419-25), while some have reporteddecreased plasma alpha-synuclein in Parkinson's patients compared withnormal controls (Li et al., Exp Neurol. 2007; 204(2):583-8).

In certain embodiments, the therapeutic agent(s) of the presentinvention is administered in combination with at least one othertherapeutic agent which is an alcohol deterrent (e.g., Acamprosate), anarcotic analgesic (e.g., Remifentanil), an anti-dyskinesia agent (e.g,Amantadine, Apomorphine, Benserazide, Bromocriptine, Cabergoline,Carbidopa, Dexetimide, Droxidopa, Entacapone, Levodopa, Lisuride,Memantine, Piribedil, Pramipexol, Ropinirole, Selegiline, Sinemet), ananti-infective agent (e.g. Amantadine, Amoxicillin, Clardthromycin,Ethanol, Interferons, Minocycline, PS-K), an anti-obesity agent (e.g.,Phenylpropanolamine, Topiramate), an anticonvulsant (e.g., Etiracetam,Topiramate), an antiemetic (e.g., Trimethobenzamide), anantihypertensive agent (e.g., Trandolapril), an antineoplastic agent(e.g., Cabergoline, PS-K), central nervous system depressant (e.g.,Aripiprazole, Benzocaine, Clozapine, Cocaine, Dexmedetomidine,Diphenhydramine, isoflurane, Lithium, Lithium Carbonate, Metylperon,Morphine, Propofol, Quetiapine, Raclopride, Remifentanil, SodiumOxybate), a central nervous system stimulant (e.g., Caffeine citrate,Modafinil, Nicotine polacrilex), a coagulant (e.g., ArginineVasopressin, Deamino Arginine Vasopressin, Vasopressins), a dermatologicagent (e.g., Loratedine, Promethazine), a gastrointestinal agent (e.g.,Diphenhydramine, Domperidone, Omeprazole, Trimethobenzamide), a hypnoticand/or sedative (e.g., Remifentanil), a micronutrient (e.g.,Alpha-Tocopherol, Coenzyme Q10, Ergocalciferols, Hydroxocobalamin, Iron,Tocopherol acetate, Tocopherols, Vitamin B 12, Vitamin D, Vitamin E), aneuroprotective agent (e.g., Eliprodil, Modafinil, Rasagiline,Rivastigmine, Topiramate), a nootropic agent (e.g., Donepezil,Etiracetam), a psychotropic drug (e.g., Aripiprazole, Citalopram,Clozapine, Duloxetine, Lithium, Lithium Carbonate, Metylperon,Nortriptyline, Paroxetine, Quetiapine, Raciopride, Venkafaxine), arespiratory system agent (e.g., Dextromethorphan, Guaifenesin,Ipratropium, Naphazoline, Oxymetazoline, Phenylephrine,Phenylpropanolamine), a vasoconstrictor agent (e.g., Naphazoline,Oxymetazoline, Phenylephrine, Phenylpropanolamine).

In one preferred embodiment, the aforementioned other therapeutic agentsare administered when the disorder is Parkinson's disease.

In certain embodiments, the therapeutic agent(s) of the presentinvention is administered in combination with at least one othertherapeutic agent which is a nicotinic alpha-7 agonist (e.g., MEM 3454or MEM 83905 both of which are available from Memory Pharmaceuticals).In certain embodiments, the therapeutic agent(s) of the presentinvention is administered in combination with at least one othertherapeutic agent which is R3487 and/or R4996 (both of which areavailable from Roche). Also contemplated are combinations of thetherapeutic agent(s) of the present invention with more than one othertherapeutic agents. Exemplary combinations of other therapeutic agentsinclude, but not are not limited to, R3487/MEM 3454 and R4996/MEM 63908.

In certain embodiments, the therapeutic agent(s) of the presentinvention is administered in combination with at least onecholinesterase inhibitor (e.g., donepezil (brand name Aricept),galantamine (brand name Razadyne), and rivastigmine (branded as Exelonand Exelon Patch).

In certain embodiments, the therapeutic agent(s) of the presentinvention is administered in combination with at least onenoncompetitive NMDA receptor antagonist (e.g., memantine (brand namesAkatinol, Axura, EblxelAbixa, Memox and Namenda)).

In certain embodiments, the therapeutic agent(s) of the presentinvention is administered in combination with at least one othertherapeutic agent which is a non-narcotic analgesic (e.g., Celecoxib,Resveratrol, Rofecoxib, TNFR-Fc fusion protein), an anti-dyskinesiaagent (e.g., Dexetimide, Gabapentin, Levodopa, Memantine), ananti-infective agent (e.g., Acetylcysteine, Acyclovir, Benzoates,Deoxyglucose, Doxycycline, Interferon Alfa-2a, Interferon-alpha,Interferons, Moxifloxacin, PS-K, Quinacrine, Rifampin, Salicylic Acid,Valacyclovir), an anti-inflammatory agent (e.g., Aspirin, Celecoxib,Curcumin, Ibuprofen, Indomethacin, Naproxen, Resveratrol, Rofecoxib,TNFR-Fc fusion protein), an anti-obesity agent (e.g.,Phenylpropanolamine), an anticonvulsant agent (e.g., Gabapentin,Homotaurine, Lamotrigine), an antiemetic (e.g., Olanzapine), anantihypertensive agent (e.g., Trandolapril), an antilipemic agent (e.g.,Atorvastatin, Choline, Clofibric Acid, Pravastatin, Simvastatin), anantineoplastic agent (e.g., Bryostatin 1, Carmustine, Cyclophosphamide,Interferon Alfa-2a, Leuprolide, Medroxyprogesterone 17-Acetate,Methyltestosterone, PK 11195, Prednisone, PS-K, Resveratrol,2,3-dihydro-1H-imidazo(1,2-b)pyrazole), an antirheumatic agent (e.g.,Aspirin, Celecoxib, Curcumin, Ibuprofen, Indomethacin, Naproxen,Resveratrol, Rofecoxib, TNFR-Fc fusion protein), a central nervoussystem depressant (e.g., Aripiprazole, Benzocaine, Cocaine, Gabapentin,Haloperidol, Haloperidol decanoate, Lithium, Lithium Carbonate,Lorazepam, Midazolam, Olanzapine, Perphenazine, Propofol, Quetiapine,Risperidone, Sodium Oxybate, Trazodone, Valproic Acid, Zolpidem), acentral nervous system stimulant (e.g., Caffeine citrate, Modafinil,Nicotine polacrilex), a channel blocker (e.g., Gabapentin, Lamotrigine),a coagulant (e.g., Antiplasmin, Vitamin K), a dermatologic agent (e.g.,Mineral Oil, Salicylic Acid), a gastrointestinal agent (e.g., Choline,Haloperidol, Lorazepam, Olanzapine, Omeprazole, TNFR-Fc fusion protein),a hypnotic and/or sedative agent (e.g., Zolpidem), a hypoglycemic agent(e.g., Insulin, Asp(B28)-, Rosiglitazone), a micronutrient (e.g.,Alpha-Tocopherol, Ascorbic Acid, Coenzyme Q10, Copper, Folic Acid,Hydroxocobalamin, Inositol, iron, Niacin, Niacinamide, Nicotinic Acids,Pyridoxine, Selenium, Thioctic Acid, Tocopherol acetate, Tocopherols,Vitamin B 12, Vitamin B 8, Vitamin E, Vitamin K), a neuroprotectiveagent (e.g., Huperzine A, Modafinil, Nefiracetam, Rasagiline,Rivastigmine, (3-aminopropyl)(n-butyl)phosphinic acid), a nootropicagent (e.g., Donepezil, Nefiracetam), a platelet aggregation inhibitor(e.g., Resveratrol), a psychotropic drug (e.g., Aripiprazole, Bupropion,Citalopram, Duloxetine, Gabapentin, Haloperidol, Haloperidol decanoate,Lithium, Lithium Carbonate, Lorazepam, Midazolam, Nefiracetam,Olanzapine, Paroxetine, Perphenazine, Quetiapine, Risperidone,Sertraline, Trazodone, Tryptophan, Valproic Acid, Venlafaxine), areproductive control agent (e.g., Estradiol 17 beta-cypionate, Estradiol3-benzoate, Estradiol valerate, indomethacin, Leuprolide,Medroxyprogesterone, Medroxyprogesterone 17-Acetate, Mifepristone), arespiratory system agent (e.g., Acetylcysteine, Dextromethorphan,Gualfenesin, Naphazoline, Oxymetazoline, Phenylephrine,Phenylpropanolamine), or a vasoconstrictor agent (e.g., Naphazoline,Oxymetazoline, Phenylephrine, Phenylpropanolamine).

What is claimed:
 1. A compound of Formula III:

wherein: R¹ is C(R²)(R³)(R⁴); R² is selected from the group consistingof hydrogen, —OH or halogen; R³ is selected from the group consisting ofhydrogen, —OH, halogen or —CH₃; R⁴ is selected from the group consistingof hydrogen, halogen, —CH₃, phenyl, fluorophenyl, methylphenyl orcyclohexylmethyl; R³ and R⁴ may join with the carbon to which they areattached to form a cycloalkyl ring, which may be optionally substitutedwith one or more halogen atoms; R⁶ is —OH; R⁸ is selected from the groupconsisting of —OH or halogen; and R¹⁰ is selected from the groupconsisting of —OH or halogen, provided that that at least one of R², R³,R⁴, R⁸ or R¹⁰ comprises a halogen.
 2. A compound selected from the groupconsisting of the following:

or a pharmaceutically acceptable salt, thereof.
 3. A kit comprising: acontainer having an effective amount of a compound of claim 2, or apharmaceutically acceptable salt, or solvate thereof, or any combinationof two or more thereof; and instructions for using the same to treat adegenerative disorder of the central nervous system or a lysosomalstorage disorder.
 4. A pharmaceutical composition comprising thecompound of claim 1 and at least one pharmaceutically acceptablecarrier.
 5. A pharmaceutical composition comprising the compound ofclaim 2 and at least one pharmaceutically acceptable carrier.